Molecular mechanisms underlying the beneficial effects of exercise and dietary interventions in the prevention of cardiometabolic diseases : Journal of Cardiovascular Medicine

Secondary Logo

Journal Logo

Supplement submission

Molecular mechanisms underlying the beneficial effects of exercise and dietary interventions in the prevention of cardiometabolic diseases

Forte, Maurizioa; Rodolico, Danieleb; Ameri, Pietroc,d; Catalucci, Danielee,f; Chimenti, Cristinag; Crotti, Liah,i; Schirone, Leonardoj; Pingitore, Annachiarak; Torella, Danielel; Iacovone, Giulianom; Valenti, Valentinam; Schiattarella, Gabriele G.n; Perrino, Cinzian; Sciarretta, Sebastianoa,j

Author Information
Journal of Cardiovascular Medicine ():10.2459/JCM.0000000000001397, December 15, 2022. | DOI: 10.2459/JCM.0000000000001397
  • Free
  • PAP

Abstract

Introduction

Metabolic disorders, such as obesity and diabetes, are increasing worldwide and represent one of the main determinants of cardiovascular diseases. According to the WHO, the prevalence of obesity tripled between 1975 and 2016, reaching pandemic proportions and representing a major socioeconomic problem as well as a challenge for healthcare systems.1 The number of diabetic people also rapidly increased in every country, from 30 to 400 million since 1985 worldwide.2 Individuals with metabolic disorders are at high risk of developing adverse cardiovascular and cerebrovascular events, such as myocardial infarction and ischemic stroke.3,4 Although the molecular mechanisms underlying the deleterious effects of cardiovascular complications induced by metabolic disorders are not completely characterized, studies performed in preclinical models of cardiometabolic diseases and in patients indicate that insulin resistance, metabolic alterations, systemic inflammation and oxidative stress are common hallmarks, which compromise cardiac and vascular function in the presence of a metabolic stress, such as hyperglycaemia and hypercholesterolemia.2,5,6 Mitochondrial dysfunction and defects of mitochondrial dynamics and autophagy are also observed.2,5,6 Targeting these mechanisms was reported to be an efficacious strategy to reduce disease progression. Several compounds acting on specific molecular players involved in mitochondrial function, autophagy and inflammation were also characterized as the integration of traditional therapies. These compounds include systemic and mitochondria-specific antioxidants, anti-inflammatory agents and natural and synthetic activators of autophagy.7,8

Cardiometabolic diseases show a complex and multifactorial etiopathogenesis, including genetic, behavioural, socioeconomic and environmental factors.3 Epidemiological data revealed that lifestyle factors, such as scarce or absent physical activity and an unbalanced diet, are also associated with an increased risk of developing cardiometabolic diseases.3,9,10 It is well documented that a diet rich in highly processed foods, as well as an excessive consumption of sugar, affects several cardiometabolic risk factors, including low-density lipoprotein (LDL) and cholesterol levels, glucose-insulin homeostasis and metabolic pathways, thereby predisposing to adverse cardiovascular events. Conversely, diets rich in fruits and vegetables were reported to reduce the risk of cardiovascular diseases.11,12 In addition to the modification of diet composition, interventions aimed at reducing calorie intake (calorie restriction) or at reprogramming the time of feeding during the day [intermittent fasting and time-restricting feeding (TRF)] were previously found to be efficacious in reducing cardiovascular complications in the presence of obesity, diabetes and metabolic syndrome.13–15 This evidence suggests that lifestyle changes aimed at modifying unhealthy dietary habits and promoting physical activity may represent powerful interventions for primary and secondary prevention of individuals at high cardiometabolic risk.

Understanding the mechanisms underlying the beneficial effects of exercise and healthy diet is also key to developing pharmacological treatments, which hold the potential to reproduce these effects.16 In this review, we discuss the current knowledge about the molecular effects of exercise and dietary restriction in preclinical models of cardiometabolic diseases and in patients, with a particular focus on oxidative stress, inflammation, mitochondrial dysfunction and autophagy.

Overview of the molecular mechanisms involved in cardiometabolic diseases

Overt type 1 and type 2 diabetes

Diabetes may directly affect cardiac structure and function independently of the presence of other risk factors, such as hypertension and coronary heart disease, causing a clinical condition termed diabetic cardiomyopathy.17 Previous lines of evidence demonstrated that both type 1 and type 2 diabetes may directly affect multiple molecular pathways in cardiac cells, finally leading to the development of myocardial oxidative stress, inflammation, cell death, mitochondrial dysfunction and metabolic derangements.18 These alterations may lead to cardiac hypertrophy, fibrosis and heart failure, in particular heart failure with preserved ejection fraction.18 However, systolic dysfunction was also observed in diabetic patients without coronary heart disease.19,20

Oxidative stress

Reactive oxygen species (ROS) directly cause cardiac hypertrophy, fibrosis and ventricular dysfunction. ROS increase in the presence of diabetes and have a direct effect on biological macromolecules, such as proteins, lipids and DNA, causing cytotoxicity. ROS-induced DNA damage leads to the accumulation of glycolytic intermediates and the activation of protein kinase C (PKC) and advanced glycation end-product (AGE) signalling, which together contribute to cardiac dysfunction.21 ROS also target sarcomere proteins thus affecting cardiomyocyte stiffness.22,23 Hyperglycaemia induces superoxide production, which reacts with nitric oxide to form peroxynitrite, resulting in reduced nitric oxide bioavailability.21 In saphenous veins and internal mammary arteries of diabetic patients undergoing coronary artery bypass surgery, the production of superoxide was reported to be dependent on the increased activity of NADPH oxidase and PKC and on the uncoupling of endothelial nitric oxide synthase (eNOS).24 Xanthine oxidase, an enzyme generating superoxide, is also activated in the heart of diabetic mice.25 Oxidative stress in diabetic myocardium is also the result of the decreased activity of the antioxidant system. In this regard, the expression of the transcription factor NF-E2-related factor 2 (Nrf2) is reduced in the hearts of streptozotocin (STZ)-induced diabetic mice,26 whereas the overexpression of antioxidant proteins improves cardiac function in experimental diabetes.27,28 ROS activate the transcription factor nuclear factor of activated T-cells (NFAT) in STZ-induced diabetic mice, which increases the expression of genes involved in atherogenesis and enhances endothelin-1-induced vasoconstriction.29,30 NFAT activation in cardiac cells during diabetes also predisposes to cardiac hypertrophy and heart failure.31 Forkhead box protein O1 (FOXO1) activity increases in response to ROS in the heart of diabetic high-fat diet (HFD)-treated mice and in diabetic (db/db) mice, resulting in the development of cardiomyopathy, whereas FOXO1 knockout mice are protected from diabetes-induced cardiomyopathy.32–34 The downregulation of insulin signalling is associated with the development of FOXO1-induced cardiomyopathy. Increased ROS production was also found to impair circadian clock synchronization of glucose and lipid metabolism.2 The overproduction of ROS during diabetes also represents a common upstream mediator of increased inflammation and mitochondrial dysfunction. These aspects will be discussed in the following sub-paragraphs.

Inflammation

Myocardial inflammation is also critical for the development of diabetic cardiomyopathy. Diabetic patients show high circulating levels of inflammatory mediators, which correlate with cardiac dysfunction.35 The increase in glucose and free fatty acids during diabetes induces the secretion of cytokines, chemokines and adhesion molecules in cardiac cells as a consequence of the activation of the nuclear factor kappa-light-chain-enhancer of activated B (NF-kB).18 Among cytokines, tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) represent two important contributors to the development of cardiac dysfunction, as their inhibition reduces leucocyte infiltration and cardiac fibrosis in STZ-treated models.36,37 TNF-α and IL-6 secretion also increase as a consequence of diabetes-induced expression of the high-mobility group box 1 (HMGB1) in cardiomyocytes, macrophages and cardiac fibroblasts.38 HMGB1 inhibition in type 1 diabetic mice improves cardiac function and decreases collagen deposition.39 Hyperglycaemia also induces macrophage secretion of inflammatory mediators and the activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-dependent inflammasome, which lead to cardiac dysfunction in a type 2 diabetic rat model induced by HFD and low dose STZ.40 In the same model, NLRP3 inhibition was found to reduce cardiac inflammation, pyroptosis, fibrosis and to improve cardiac function.40 NLRP3 inflammasome is activated also by NF-kB in type 2 diabetic models.40

Another mechanism involved in the pro-inflammatory effects of hyperglycaemia is the increase in substrates for the enzyme O-GlcNActransferase (OGT), which activates the calcium/calmodulin-dependent protein kinase IIδ (CaMKII), thereby impairing cardiac calcium handling and causing delayed afterdepolarizations in cardiomyocytes.2

Mitochondrial dysfunction

Mitochondrial dysfunction is also a hallmark of diabetes-induced cardiovascular abnormalities. Proteomic analysis of diabetic rat hearts revealed a reduced expression of proteins of the electron transport chain.17 Oxidative stress in the heart of diabetic mice was also found to increase tyrosine nitration of mitochondrial proteins, altering their structure and function and producing dysfunctional mitochondria.41 In this regard, overexpression of ROS scavengers was reported to reduce mitochondrial dysfunction and to improve cardiac function in STZ-treated mice.42

Mitochondrial dynamics, which include the process of fission, fusion and mitophagy, are also altered in diabetic models, representing a cause of mitochondrial dysfunction. Mitochondria undergo coordinated cycles of fission and fusion. Mitochondrial fission occurs when mitochondria are irreversibly damaged, whereas mitochondrial fusion is activated in the presence of reversibly damaged mitochondria. Fission-induced fragmented mitochondria are then digested by mitophagy, the selective form of autophagy for mitochondria (as further described in the text).43 Accumulating lines of evidence also demonstrated that an imbalance between fission and fusion plays a detrimental role in the cardiovascular system.43 Generally, mitochondrial fission increases, whereas fusion decreases in diabetic cardiomyopathy and in models of insulin resistance.44,45 In the myocardium of patients with type 1 diabetes mellitus, a decreased expression of mitofusin 1, a protein involved in mitochondrial fusion, was observed and inhibition of mitochondrial fission was reported to rescue cardiac dysfunction induced by lipid overload in mice.44–46 The alteration of mitochondrial dynamics observed in diabetic models also affects mitochondrial function, compromising the activity of mitochondrial electron transport chain and ATP synthesis.2

Obesity and metabolic syndrome

The accumulation of pericardial fat during obesity contributes to increased left ventricular mass and cardiac workload, often resulting in left ventricular systolic and diastolic dysfunction.4 Obesity impairs cardiac electrophysiology, leading to contractile dysfunction and atrial fibrillation.47,48 Additional physiological effects induced by obesity include an increase in blood volume and blood pressure, as a consequence of sodium retention. The latter is caused by the activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), by hyperinsulinemia and by natriuretic peptide level downregulation.49–52

Inflammation

Among the molecular mechanisms underlying obesity-induced cardiomyopathy, a release of inflammatory mediators (adipokines) by adipose cells plays a major role. Adipokines contribute to the development of systemic inflammation and insulin resistance, the main mediators of cardiac dysfunction.53,54 An increase in pro-inflammatory adipokines was found to activate cardiomyocyte signalling cascades responsible for the development of left ventricular hypertrophy and systolic dysfunction.55,56 An activation of immune cells also contributes to cardiomyopathy during obesity. Macrophage-induced release of pro-inflammatory cytokines, such as TNF-α and IL-6, has a direct effect on cardiomyocytes, since it stimulates the mitogen-activated protein kinase (MAPK) and NF-κB signalling and inhibits Akt.57,58 A deregulation of these pathways was previously found to be associated with maladaptive remodelling. Macrophages also induce extracellular matrix degradation and collagen deposition by cardiac fibroblasts.57,58

The role of NLRP3 inflammasome was also reported in the development of obesity-induced atrial fibrillation. NLRP3 is activated in the atrial tissue of obese mice and patients and NLRP3 knockout mice undergoing HFD-induced obesity show a reduced atrial fibrillation occurrence.59 These results suggest that selective inhibition of the NLRP3 inflammasome may be a promising strategy to reduce the risk of atrial fibrillation in obese people, independently of body weight reduction.

Obesity and metabolic syndrome also affect vascular function, leading to the reduction of oxygen delivery to hearts and other systemic districts.60 Individuals with obesity or metabolic syndrome are characterized by coronary microvascular dysfunction.60–63 Obesity-induced low-grade inflammation leads to atherosclerosis in patients.64 In particular, pro-inflammatory adipokines modulate several key mechanisms involved in atherogenesis. Perivascular adipose tissue accumulation during obesity and metabolic syndrome impairs endothelial function, in a mechanism mediated by PKC-β activation.65 The increased activity of TNF-α during obesity also induces vascular remodelling, impairs endothelium-dependent vasodilation and leads to cell infiltration, due to increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1).66 In addition, obesity enhances endothelin-1-mediated vasoconstriction.67

Cardiac metabolism

During obesity, cardiac metabolism exhibits a marked preference towards fatty acid oxidation (FAO).68 The overload of substrates may lead to lipotoxicity, due to the accumulation of triglyceride products, such as ceramide and DAG, which induce cardiac dysfunction.69–71 Increased FAO and lipid accumulation also contribute to cardiac insulin resistance.72 The increase in FAO observed in diabetes can be attributed to the enhanced fatty acid supply and uptake by cardiomyocytes and to the increased transcription of fatty acid metabolic enzymes. In fact, lipid accumulation activates peroxisome proliferator-activated receptor-a (PPARa), which increases the expression of genes involved in fatty acids metabolism.71 Mice with overexpression of PPARa show cardiac hypertrophy and contractile dysfunction, whereas PPAR-deficient models display reduced myocardial FAO.72

Mitochondrial dynamics and autophagy

Mitochondrial dysfunction also contributes to obesity-induced cardiomyopathy, along with altered mitochondrial dynamics and mitophagy.73 HFD-treated mice show increased cardiac mitochondrial fission, due to the activation of dynamin related protein 1 (Drp-1), a marker of mitochondrial fission, which in turn contributes to cardiomyocyte cell death.74 Obesity also impairs cardiac autophagy, leading to cardiac dysfunction.75–77 Autophagy is an evolutionarily conserved intracellular mechanism by which cells digest and recycle senescent or damaged cytoplasmic elements, including whole organelles. In recent years, autophagy has emerged as a pivotal mechanism in mediating stress response in the cardiovascular system, by limiting damage and preserving cellular integrity.78 Autophagy is initially activated in cardiomyocytes in response to short-term feeding with HFD, whereas it is progressively inhibited by chronic feeding. Autophagy reactivation attenuates the detrimental effects of obesity in the heart. Conversely, mitophagy, a specialized form of autophagy devoted to the removal of damaged mitochondria, progressively increases in HFD-induced obesity by the activation of the ULK1/RAB9 pathway, although in an insufficient manner.79,80 A pharmacological boosting of mitophagy attenuates obesity-induced cardiac dysfunction.79,80

Exercise and cardiometabolic diseases

Preclinical studies

Although physical exercise leads to adaptive cardiac remodelling and hypertrophy, a condition that is frequent in the athlete's heart, several studies demonstrated that regular and moderate physical activity elicits cardiovascular benefits in models of cardiometabolic diseases and in patients. In the apolipoprotein E–knockout (apoE−/−) mouse strain, a relevant model for the study of obesity and metabolic syndrome, physical exercise over a period of 6 weeks was reported to reduce neointimal growth and to stabilize vascular lesions in response to carotid artery injury and thrombosis.81 In LDL–receptor–deficient (LDLR−/−) mice fed with a high cholesterol diet, regular exercise reduced the thickness of the aortic valve and improved endothelial function. The beneficial effects observed in this study are associated with reduced systemic levels of oxidative stress and ROS generation in the aortic valve.82 It has been reported that ApoE -/- mice fed with a high cholesterol diet undergoing exercise show improved endothelial function and reduced atherosclerotic plaque formation. In the same study, the authors found a reduced activity of RAC1 and NADPH oxidase, the main source of superoxide, in the vascular wall.83 In the same animal model, swimming training was found to reduce atherosclerosis and rescue nitric oxide metabolism.84 Similar results were obtained in a mouse model of type 2 diabetes, wherein exercise promoted cardiac expression of eNOS and decreased superoxide production.85 In mice treated with a HFD, running improves endothelial function and mitochondrial biogenesis, due to Nox4-mediated release of hydrogen peroxide. Indeed, the protective effects of exercise were lost in systemic Nox4 knockout mice (Nox4 –/–). This evidence suggests that Nox4 is required for exercise-induced cardiovascular adaptations.86 Overall, these studies indicate that exercise reduces cardiovascular complications of obesity and diabetes through the regulation of oxidative stress and the improvement of nitric oxide metabolism.

In the hearts of diabetic aged mice, short-term exercise was reported to increase the expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, a transcription factor that promotes mitochondrial biogenesis. In addition, exercised mice show reduced levels of pro-inflammatory cytokines and cardiac inflammation.87 Exercise rescues cardiomyopathy in diabetic rats and these effects are associated with reduced cardiac apoptosis and endoplasmic reticulum stress.88 Moderate-intensity exercise improves cardiac function in type 2 diabetic mice (db/db), by enhancing gap junction communication and by reducing levels of Drp1.89 The attenuation of mitochondrial dysfunction and damage was also observed in streptozotocin-induced diabetic rats and in mice fed with diet-induced obesity (DIO).90,91 Another mechanism underlying the reduction of ROS elicited by exercise is the increased expression of cardiac mitochondrial uncoupling protein 2 (UCP2), an inner mitochondrial membrane protein that lowers mitochondrial membrane potential, thus dissipating heat and preventing ROS accumulation.92 In db/db mice, it has been shown that the progression of diabetic heart disease is attenuated when exercise is initiated before the onset of cardiac dysfunction, due to the reduction of cardiac apoptosis, fibrosis and microvascular rarefaction. In contrast, these beneficial effects are not evident if exercise is introduced when cardiac dysfunction is already established.93 Exercise training also increases glucose utilization in the hearts of diabetic rats94 and rescues contractile dysfunction in db/db mice through the restoration of calcium release by the sarcoplasmic reticulum.95

Notably, a recent study showed that voluntary running restores cardiomyogenesis in aged mice, highlighting that exercise may have remarkable effects also on cardiomyocyte self-renewal.96

Other evidence suggests that exercise modulates cardiac autophagy. Eight weeks of exercise training rescue cardiac autophagy and autophagic flux in a model of myocardial infarction, along with the improvement of mitochondrial bioenergetics.97 In a mouse model of autophagy deficiency, termed BCL2 AAA, long-term exercise training fails to protect from high-fat diet-induced glucose intolerance, suggesting that autophagy mediates the beneficial effects of exercise in the presence of metabolic stress.98 In a recent study, 16 weeks of exercise was demonstrated to reduce atherosclerosis in Apo E –/– mice fed with a HFD and to stimulate aortic endothelial autophagy, without affecting systemic levels of triglycerides and total cholesterol.99 Further studies should test whether the protective effects of exercise in models of atherosclerosis are blunted in the presence of autophagy inhibition. The molecular effects of exercise in cardiometabolic diseases are illustrated in Fig. 1.

F1
Fig. 1:
Molecular and cellular effects of exercise in animal models of cardiometabolic diseases and in patients. The net result of systemic and cell-specific effects of exercise is the improvement of cardiac and vascular function. NO, nitric oxide. The figure was made using tools provided by Servier Medical Arts, amongst others.

Clinical studies

Preclinical evidence about the role of physical exercise in the reduction of cardiovascular complications in cardiometabolic diseases are confirmed by human studies. Elite athletes show higher life-expectancy than the general population and also show reduced risk of cardiovascular mortality.100 Five to ten minutes per day of running, even at slow speed, reduce the risk of death and cardiovascular disease in healthy individuals.101 Similarly, physical activity was reported to reduce the risk of cardiovascular mortality in obese people and in men with type 2 diabetes.102–104 The protective effects of exercise on vascular function were demonstrated in different trials. Exercise improves endothelial function in overweight and obese adults.105,106 For instance, 8th weeks of combined aerobic and resistance exercise training ameliorates endothelial function in diabetic patients.107 Another study shows that 6 months of aerobic exercise fail to rescue microvascular dysfunction in diabetic people,108 but they are able to reduce the thickness of carotid intima-media in patients with type 2 diabetes mellitus, along with the improvement of glycaemic control, blood pressure level and BMI.109 Endurance exercise also improves endothelial function in patients with coronary artery disease (CAD), increases nitric oxide bioavailability and enhances large artery elasticity in overweight and obese older adults.110–112

Other studies investigated the effects of exercise on cardiac function in humans. The CARDIO-FIT trial showed that physical activity reduces the risk of atrial fibrillation in overweight and obese individuals with symptomatic atrial fibrillation.113 In obese patients with heart failure with preserved ejection fraction (HFPEF), aerobic exercise training increases peak oxygen consumption and reduces systemic inflammation and left ventricular mass.114 A reduction of markers of inflammation, such as C-reactive protein (CRP) and IL-6, is also observed in diabetic patients.115 Physical activity also induces weight loss in obese individuals and reduces insulin resistance.116 In this regard, weight loss following 8 weeks of exercise correlates with the improvement of subclinical cardiovascular dysfunction in obese individuals.117 Other effects on metabolism include the control of glycaemic levels and insulin sensitivity.118 Overall, this evidence suggests that physical activity exerts beneficial effects in cardiac and vascular cells by acting on nitric oxide metabolism, oxidative stress and inflammation, which may be in part dependent on the reduction of adipose tissue and insulin resistance. The modulation of mitochondrial dynamics in response to exercise was also observed in patients. Exercise promotes mitochondrial fusion and decreases mitochondrial fission in human muscle skeletal biopsies and also increases markers of general autophagy.119,120 An upregulation of autophagy was also observed in peripheral blood mononuclear cells (PBMCs) isolated from individuals undergoing short-term exercise.121 In a recent study, exercise upregulates the expression of autophagic markers in the adipose tissue of obese and diabetic patients.122 However, in another study, autophagy markers were not modulated in skeletal muscle biopsies of type 2 diabetic patients undergoing exercise.123,124 Further studies should correlate the levels of circulating markers of autophagy with vascular and cardiac function in obese and diabetic individuals undergoing exercise, in addition to muscle cells and PBMCs.

Dietary restriction and cardiometabolic disease

Preclinical studies

Dietary restriction represents another promising intervention for the prevention of cardiovascular complications induced by obesity, diabetes and metabolic syndrome. Calorie restriction, defined as the reduction of calorie intake (30–40% of reduction) without malnutrition, was reported to elicit health-promoting effects in chronic diseases, such as neurodegenerative disease and cancer.125 CR exerts important antiageing effects. In this regard, calorie restriction increases lifespan and reduces cardiovascular ageing in different organisms.126 Calorie restriction also modulates cellular metabolism. The latter includes changes in the lipid profile, such as the reduction of triglycerides and LDL cholesterol, as well as the reduction of glucose and insulin levels and the improvement of insulin sensitivity. Other evidence points to the effects of calorie restriction on the endocrine system, wherein it reduces the secretion of insulin-like growth factor-binding protein 1 (IGFBP1) and angiotensin I.127 Calorie restriction also reduces inflammation, mitochondrial dysfunction and oxidative stress, whereas it activates autophagy in the cardiovascular system.8 Additional molecular effects of calorie restriction are mediated by the modulation of nutrient-sensing pathways. Calorie restriction activates 5’ adenosine monophosphate-activated protein kinase (AMPK), histone (de)acetylase sirtuin1 (SIRT1), and protein kinase B (PKB, also known as Akt) and inhibits the insulin/IGF1-like signalling pathway (IIS) and the mammalian target of rapamyicin complex (mTORC)1.8 These signalling cascades are known modulators of autophagy. The physiological consequences of the metabolic and molecular effects of calorie restriction are the improvement of endothelial function and heart rate variability, as well as the reduction of low-intima-media thickness and blood pressure levels.8

The effects of calorie restriction were studied in models of cardiometabolic diseases. The incidence of cardiovascular diseases and diabetes was lower in rhesus monkeys undergoing calorie restriction.128,129 In db/db mice, calorie restriction was found to reduce cardiac fibrosis and leukocytes infiltration and markers of toll-like receptors (TLRs) activation and to rescue serum levels of free fatty acids.130 In the same animal model, the protective effects of calorie restriction were associated with the restoration of SIRT1 and PGC1-alpha activity.131 Mild (20% food intake reduction) and short-term (2 weeks) calorie restriction was reported to reduce cardiac issues in obese rats and this effect was independent of the modulation of the cardiac metabolic profile.132 Another study demonstrated that calorie restriction for 4 months rescues cardiac dysfunction in younger obese mice, but fails to exert the same effects in older animals. The beneficial effects observed in younger obese mice were attributable to the decrease in oxidative stress and to the improvement of NOS activity.133 Other reports demonstrated that calorie restriction is able to rescue cardiac dysfunction in diabetic and obese mice and rats and this effect is associated with the improvement of autophagy.134,135 Combined calorie restriction and exercise were found to improve cardiac function in obese insulin-resistant rats and rescue mitochondrial dysfunction and apoptosis in the heart. Remarkably, the cardiac protective effects of calorie restriction as well as exercise were more pronounced if compared with the single intervention.136 Calorie restriction also exerts vascular protective effects. Calorie restriction reduces atherosclerotic lesions and levels of oxidative stress in the aorta of Apo E –/– mice, whereas it rescues endothelial function and autophagic flux in the aorta of db/db mice.137,138 The molecular effects of calorie restriction in cardiometabolic diseases are summarized in Fig. 2.

F2
Fig. 2:
Molecular and cellular effects of calorie restriction in animal models of cardiometabolic diseases and in human. The net result of systemic and cell-specific effects of calorie restriction is the improvement of cardiac and vascular function. NO, nitric oxide. The figure was made using tools provided by Servier Medical Arts, amongst others.

Intermittent fasting, characterized by the alternation of fasting and re-feeding cycles, also exerts beneficial effects in models of obesity and diabetes.139 Six months of intermittent fasting reduces cardiovascular risk factors in rats.140 TRF [for animals and time-restricted eating (TRE) for patients] represents a form of intermittent fasting that maintains a daily cycle of feeding and fasting with a circadian rhythm (Fig. 3). Irregular eating times have been reported to increase cardiovascular risk factors.141,142 Accordingly, disruption of circadian genes affects glucose and lipid homeostasis, insulin resistance and other hallmarks of metabolic disease.143 The metabolic effects of intermittent fasting and TRF are represented by a shift from fat to ketone metabolism and modulation of cellular adaptive responses, such as autophagy.144–146

F3
Fig. 3:
Schematic representation of dietary restriction interventions. In the figure are schematized common forms of Intermittent fasting, such as alternate-day feeding and time-restricted feeding. The figure was made using tools provided by Servier Medical Arts, amongst others.

Previous studies demonstrated that TRF prevents DIO and metabolic disorders in mice.147–149 From a molecular point of view, TRF affects the mTOR, AMPK and CREB pathways in the liver150 and also restores the expression of genes regulating circadian rhythm.151 Studies performed in Drosophila revealed that TRF exerts cardiovascular protective effects. In this model, TRF was found to reduce cardiac ageing and high-fat diet-induced cardiac dysfunction. The cardiac protective effects of TRF were mediated by the increased expression of genes encoding for the TCP-1 Ring Complex (TRiC) chaperonin and by the reduced expression of genes encoding for the mitochondrial electron transport chain complexes.148 Finally, TRF during the light-phase was reported to rescue the circadian rhythm of blood pressure levels through the inhibition of sympathetic activity in obese mice.152 Further studies should investigate cardiac and vascular molecular effects of intermittent fasting and TFR in mouse and rat models of cardiometabolic diseases.

Clinical studies

Dietary restriction protocols were also tested in human clinical trials. Long-term calorie restriction was reported to improve diastolic function in healthy individuals and to reduce markers of inflammation, fibrosis and blood pressure levels.153,154 Six-month calorie restriction induces weight loss and reduces cardiovascular risk in healthy nonobese individuals.155 In line with this evidence, long-term CR (6 years) was reported to reduce the risk of atherosclerosis, highlighted by the reduction of carotid artery intima-media thickness (IMT).156 Calorie restriction improves cardiovascular function in type 2 diabetic and obese patients with CAD, along with the reduction of body weight.157 The reduction of risk factors for the development of CAD was also observed in nonobese subjects undergoing calorie restriction.158 The CALERIE study demonstrated that CR reduces blood pressure levels and lipid profile in healthy, nonobese individuals159 and it also improves biomarkers of longevity, metabolic adaptation and oxidative stress in overweight individuals.160,161 The protective effects of calorie restriction are also those mediated by the reduction of autonomic function, which in turn improves heart rate variability.162 In patients with type 2 diabetes, calorie restriction was found to reduce sympathetic tone and RAAS activity.163 Calorie restriction also inhibits the IGF-1/insulin pathway and improves levels of autophagic markers and mediators of quality control mechanisms in skeletal muscle.164,165 It would be interesting to evaluate in the future whether these pathways are also modulated in the heart and vessels of individuals with cardiometabolic diseases.

The protective effects of intermittent fasting and TRE were also observed in patients. Intermittent fasting reduces cardiovascular risk factors in young overweight women.166 An intermittent fasting protocol consisting of calorie consumption limited to 8 h during day-time was reported to reduce cardiovascular risk factors in resistance-trained men.167 Early TRE in the morning also improves insulin sensitivity, and reduces blood pressure levels and oxidative stress in men with prediabetes.168 Consistently with this, 10-h TRE for 12 weeks reduces blood pressure and LDL cholesterol levels in patients with metabolic syndrome.169 Alternate-day fasting, another form of intermittent fasting, also decreases cardiovascular risk factors in obese adults.170

Conclusion and future perspectives

The evidence gathered here suggests that lifestyle interventions, such as exercise and dietary restriction or a combination of both reduce cardiovascular complications of obesity and diabetes, both in preclinical models and in patients. In summary, exercise and dietary restriction rescue cell metabolism, with a net result of weight loss and also reduce systemic inflammation and oxidative stress. Exercise and dietary restriction also target specific molecular mechanisms, such as autophagy and mitochondrial dynamics. However, some studies failed to dissect whether the protective effects exerted by exercise or calorie restriction in the cardiovascular systems are mediated by systemic or cell-specific effects. Mechanistic studies should clarify this aspect, by evaluating, for example, the effects of calorie restriction and exercise in loss-of-function models of autophagy or circadian genes.

The clinical application of exercise and dietary modifications to patients with cardiometabolic diseases also presents some limitations. People may be reluctant to adopt a correct lifestyle or to perform regular physical activity, showing low compliance to specific diet or training recommendations. To overcome this problem, several compounds, both natural and synthetic, called calorie restriction mimetics (CRM), mimic the physiological and molecular effects of calorie restriction and could be used in place of calorie restriction and exercise.8 Multiple lines of evidence demonstrated that different CRM are able to improve cardiac function and reduce ageing in preclinical models of cardiovascular diseases.8 At a molecular level, CRM were reported to reduce the acetylation of intracellular proteins leading to nutrient depletion and autophagy activation.171 Spermidine, a polyamine present in different foods, such as soybeans and nuts, is a promising CRM that was found to extend lifespan in mice and to reduce cardiac complications induced by ageing in an autophagy/mitophagy-dependent manner.172 Remarkably, epidemiological data revealed that dietary intake of spermidine is associated with low incidence of cardiovascular diseases and increased longevity in individuals.172,173 Other CRM, such as rapamycin, resveratrol, curcumin and epigallocatechin-3-gallate were also found to improve cardiac function in mouse models of type 2 diabetes and obesity.174–178 It will be interesting to compare the cardiovascular effects of CRM and dietary restriction interventions in clinical trials. Moreover, CRM are generally well tolerated, in some cases already FDA-approved, and for these reasons, they may be introduced as adjuvants of traditional therapy or as preventive tools for reducing cardiometabolic risk factors.

Acknowledgements

The authors thank the Italian Society of Cardiology for the continuous support to the activities of the study group, including the preparation of this manuscript.

Conflicts of interest

There are no conflicts of interest.

References

1. Collaboration NCDRF Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet 2017; 390:2627–2642.
2. Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res 2016; 118:1808–1829.
3. Bhupathiraju SN, Hu FB. Epidemiology of obesity and diabetes and their cardiovascular complications. Circ Res 2016; 118:1723–1735.
4. Ren J, Wu NN, Wang S, Sowers JR, Zhang Y. Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications. Physiol Rev 2021; 101:1745–1807.
5. Tune JD, Goodwill AG, Sassoon DJ, Mather KJ. Cardiovascular consequences of metabolic syndrome. Transl Res 2017; 183:57–70.
6. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444:875–880.
7. Voglhuber J, Ljubojevic-Holzer S, Abdellatif M, Sedej S. Targeting cardiovascular risk factors through dietary adaptations and caloric restriction mimetics. Front Nutr 2021; 8:758058.
8. Sciarretta S, Forte M, Castoldi F, et al. Caloric restriction mimetics for the treatment of cardiovascular diseases. Cardiovasc Res 2021; 117:1434–1449.
9. Lavie CJ, Ozemek C, Carbone S, Katzmarzyk PT, Blair SN. Sedentary behavior, exercise, and cardiovascular health. Circ Res 2019; 124:799–815.
10. Pinckard K, Baskin KK, Stanford KI. Effects of exercise to improve cardiovascular health. Front Cardiovasc Med 2019; 6:69.
11. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med 2011; 364:2392–2404.
12. Smith JD, Hou T, Ludwig DS, Rimm EB, Willett W, Hu FB, et al. Changes in intake of protein foods, carbohydrate amount and quality, and long-term weight change: results from 3 prospective cohorts. Am J Clin Nutr 2015; 101:1216–1224.
13. Schuppelius B, Peters B, Ottawa A, Pivovarova-Ramich O. Time restricted eating: a dietary strategy to prevent and treat metabolic disturbances. Front Endocrinol (Lausanne) 2021; 12:683140.
14. Lamos EM, Malek R, Munir KM. Effects of intermittent fasting on health, aging, and disease. N Engl J Med 2020; 382:1771.
15. Oza MJ, Laddha AP, Gaikwad AB, Mulay SR, Kulkarni YA. Role of dietary modifications in the management of type 2 diabetic complications. Pharmacol Res 2021; 168:105602.
16. Mann N, Rosenzweig A. Can exercise teach us how to treat heart disease? Circulation 2012; 126:2625–2635.
17. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007; 115:3213–3223.
18. Frati G, Schirone L, Chimenti I, Yee D, Biondi-Zoccai G, Volpe M, et al. An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy. Cardiovasc Res 2017; 113:378–388.
19. Palmieri V, Bella JN, Arnett DK, Liu JE, Oberman A, Schuck MY, et al. Effect of type 2 diabetes mellitus on left ventricular geometry and systolic function in hypertensive subjects: Hypertension Genetic Epidemiology Network (HyperGEN) study. Circulation 2001; 103:102–107.
20. Zarich SW, Arbuckle BE, Cohen LR, Roberts M, Nesto RW. Diastolic abnormalities in young asymptomatic diabetic patients assessed by pulsed Doppler echocardiography. J Am Coll Cardiol 1988; 12:114–120.
21. Cave AC, Brewer AC, Narayanapanicker A, et al. NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 2006; 8:691–728.
22. Santos CX, Anilkumar N, Zhang M, Brewer AC, Shah AM. Redox signaling in cardiac myocytes. Free Radic Biol Med 2011; 50:777–793.
23. Steinberg SF. Oxidative stress and sarcomeric proteins. Circ Res 2013; 112:393–405.
24. Guzik TJ, Mussa S, Gastaldi D, et al. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 2002; 105:1656–1662.
25. Rajesh M, Mukhopadhyay P, Batkai S, et al. Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy. J Cell Mol Med 2009; 13 (8B):2330–2341.
26. Tan Y, Ichikawa T, Li J, et al. Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes 2011; 60:625–633.
27. Wold LE, Ceylan-Isik AF, Fang CX, et al. Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme. Free Radic Biol Med 2006; 40:1419–1429.
28. Ye G, Metreveli NS, Donthi RV, et al. Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes 2004; 53:1336–1343.
29. Zetterqvist AV, Berglund LM, Blanco F, et al. Inhibition of nuclear factor of activated T-cells (NFAT) suppresses accelerated atherosclerosis in diabetic mice. PLoS One 2014; 8:e65020.
30. Friedman JK, Nitta CH, Henderson KM, et al. Intermittent hypoxia-induced increases in reactive oxygen species activate NFATc3 increasing endothelin-1 vasoconstrictor reactivity. Vascul Pharmacol 2014; 60:17–24.
31. Bourajjaj M, Armand AS, da Costa Martins PA, et al. NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure. J Biol Chem 2008; 283:22295–22303.
32. Eijkelenboom A, Burgering BM. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 2013; 14:83–97.
33. Ozcan L, Wong CC, Li G, Xu T, Pajvani U, Park SK, et al. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab 2012; 15:739–751.
34. Battiprolu PK, Hojayev B, Jiang N, et al. Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest 2012; 122:1109–1118.
35. Sciarretta S, Ferrucci A, Ciavarella GM, et al. Markers of inflammation and fibrosis are related to cardiovascular damage in hypertensive patients with metabolic syndrome. Am J Hypertens 2007; 20:784–791.
36. Westermann D, Van Linthout S, Dhayat S, et al. Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 2007; 102:500–507.
37. Zhang Y, Wang JH, Zhang YY, et al. Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFbeta1 and miR-29 pathways. Sci Rep 2016; 6:23010.
38. Volz HC, Seidel C, Laohachewin D, et al. HMGB1: the missing link between diabetes mellitus and heart failure. Basic Res Cardiol 2010; 105:805–820.
39. Wang WK, Wang B, Lu QH, et al. Inhibition of high-mobility group box 1 improves myocardial fibrosis and dysfunction in diabetic cardiomyopathy. Int J Cardiol 2014; 172:202–212.
40. Luo B, Li B, Wang W, et al. NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS One 2014; 9:e104771.
41. Turko IV, Li L, Aulak KS, Stuehr DJ, Chang JY, Murad F. Protein tyrosine nitration in the mitochondria from diabetic mouse heart. Implications to dysfunctional mitochondria in diabetes. J Biol Chem 2003; 278:33972–33977.
42. Cai L, Wang Y, Zhou G, et al. Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol 2006; 48:1688–1697.
43. Forte M, Schirone L, Ameri P, et al. The role of mitochondrial dynamics in cardiovascular diseases. Br J Pharmacol 2021; 178:2060–2076.
44. Montaigne D, Marechal X, Coisne A, et al. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 2014; 130:554–564.
45. Parra V, Verdejo HE, Iglewski M, et al. Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFkappaB-Opa-1 signaling pathway. Diabetes 2014; 63:75–88.
46. Kolleritsch S, Kien B, Schoiswohl G, et al. Low cardiac lipolysis reduces mitochondrial fission and prevents lipotoxic heart dysfunction in Perilipin 5 mutant mice. Cardiovasc Res 2020; 116:339–352.
47. Cavalera M, Wang J, Frangogiannis NG. Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. Transl Res 2014; 164:323–335.
48. Lavie CJ, Pandey A, Lau DH, Alpert MA, Sanders P. Obesity and atrial fibrillation prevalence, pathogenesis, and prognosis: effects of weight loss and exercise. J Am Coll Cardiol 2017; 70:2022–2035.
49. Alpert MA, Lavie CJ, Agrawal H, Aggarwal KB, Kumar SA. Obesity and heart failure: epidemiology, pathophysiology, clinical manifestations, and management. Transl Res 2014; 164:345–356.
50. Rust P, Ekmekcioglu C. Impact of salt intake on the pathogenesis and treatment of hypertension. Adv Exp Med Biol 2017; 956:61–84.
51. Kawarazaki W, Fujita T. The role of aldosterone in obesity-related hypertension. Am J Hypertens 2016; 29:415–423.
52. Hattori T, Murase T, Takatsu M, et al. Dietary salt restriction improves cardiac and adipose tissue pathology independently of obesity in a rat model of metabolic syndrome. J Am Heart Assoc 2014; 3:e001312.
53. Ray I, Mahata SK, De RK. Obesity: an immunometabolic perspective. Front Endocrinol (Lausanne) 2016; 7:157.
54. Wu H, Ballantyne CM. Metabolic inflammation and insulin resistance in obesity. Circ Res 2020; 126:1549–1564.
55. Norman G, Norton GR, Libhaber CD, et al. Independent associations between resistin and left ventricular mass and myocardial dysfunction in a community sample with prevalent obesity. Int J Cardiol 2015; 196:81–87.
56. McManus DD, Lyass A, Ingelsson E, et al. Relations of circulating resistin and adiponectin and cardiac structure and function: the Framingham Offspring Study. Obesity (Silver Spring) 2012; 20:1882–1886.
57. Mouton AJ, Li X, Hall ME, Hall JE. Obesity, hypertension, and cardiac dysfunction: novel roles of immunometabolism in macrophage activation and inflammation. Circ Res 2020; 126:789–806.
58. Hulsmans M, Sager HB, Roh JD, et al. Cardiac macrophages promote diastolic dysfunction. J Exp Med 2018; 215:423–440.
59. Scott L Jr, Fender AC, Saljic A, et al. NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias. Cardiovasc Res 2021; 117:1746–1759.
60. Berwick ZC, Dick GM, Tune JD. Heart of the matter: coronary dysfunction in metabolic syndrome. J Mol Cell Cardiol 2012; 52:848–856.
61. Knudson JD, Dincer UD, Bratz IN, Sturek M, Dick GM, Tune JD. Mechanisms of coronary dysfunction in obesity and insulin resistance. Microcirculation 2007; 14 (4-5):317–338.
62. Prakash R, Mintz JD, Stepp DW. Impact of obesity on coronary microvascular function in the Zucker rat. Microcirculation 2006; 13:389–396.
63. Di Carli MF, Charytan D, McMahon GT, Ganz P, Dorbala S, Schelbert HR. Coronary circulatory function in patients with the metabolic syndrome. J Nucl Med 2011; 52:1369–1377.
64. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105:1135–1143.
65. Payne GA, Kohr MC, Tune JD. Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. Br J Pharmacol 2012; 165:659–669.
66. Zhang H, Park Y, Wu J, et al. Role of TNF-alpha in vascular dysfunction. Clin Sci (Lond) 2009; 116:219–230.
67. Engin A. Endothelial dysfunction in obesity. Adv Exp Med Biol 2017; 960:345–379.
68. Kolwicz SC Jr, Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res 2013; 113:603–616.
69. Zhang Y, Ren J. Role of cardiac steatosis and lipotoxicity in obesity cardiomyopathy. Hypertension 2011; 57:148–150.
70. Rayner JJ, Banerjee R, Holloway CJ, et al. The relative contribution of metabolic and structural abnormalities to diastolic dysfunction in obesity. Int J Obes (Lond) 2018; 42:441–447.
71. Finck BN, Han X, Courtois M, et al. A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci U S A 2003; 100:1226–1231.
72. Fukushima A, Lopaschuk GD. Cardiac fatty acid oxidation in heart failure associated with obesity and diabetes. Biochim Biophys Acta 2016; 1861:1525–1534.
73. Wang D, Yin Y, Wang S, et al. FGF1(DeltaHBS) prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression. Signal Transduct Target Ther 2021; 6:133.
74. Hu Q, Zhang H, Gutierrez Cortes N, et al. Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction. Circ Res 2020; 126:456–470.
75. Zhang Y, Xu X, Ren J. MTOR overactivation and interrupted autophagy flux in obese hearts: a dicey assembly? Autophagy 2013; 9:939–941.
76. Castaneda D, Gabani M, Choi SK, et al. Targeting autophagy in obesity-associated heart disease. Obesity (Silver Spring) 2019; 27:1050–1058.
77. Trivedi PC, Bartlett JJ, Perez LJ, et al. Glucolipotoxicity diminishes cardiomyocyte TFEB and inhibits lysosomal autophagy during obesity and diabetes. Biochim Biophys Acta 2016; 1861 (12 Pt A):1893–1910.
78. Sciarretta S, Maejima Y, Zablocki D, Sadoshima J. The role of autophagy in the heart. Annu Rev Physiol 2018; 80:1–26.
79. Tong M, Saito T, Zhai P, et al. Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy. Circ Res 2019; 124:1360–1371.
80. Tong M, Saito T, Zhai P, et al. Alternative mitophagy protects the heart against obesity-associated cardiomyopathy. Circ Res 2021; 129:1105–1121.
81. Pynn M, Schafer K, Konstantinides S, Halle M. Exercise training reduces neointimal growth and stabilizes vascular lesions developing after injury in apolipoprotein e-deficient mice. Circulation 2004; 109:386–392.
82. Matsumoto Y, Adams V, Jacob S, Mangner N, Schuler G, Linke A. Regular exercise training prevents aortic valve disease in low-density lipoprotein-receptor-deficient mice. Circulation 2010; 121:759–767.
83. Laufs U, Wassmann S, Czech T, et al. Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25:809–814.
84. Okabe TA, Shimada K, Hattori M, et al. Swimming reduces the severity of atherosclerosis in apolipoprotein E deficient mice by antioxidant effects. Cardiovasc Res 2007; 74:537–545.
85. Grijalva J, Hicks S, Zhao X, et al. Exercise training enhanced myocardial endothelial nitric oxide synthase (eNOS) function in diabetic Goto-Kakizaki (GK) rats. Cardiovasc Diabetol 2008; 7:34.
86. Brendel H, Shahid A, Hofmann A, et al. NADPH oxidase 4 mediates the protective effects of physical activity against obesity-induced vascular dysfunction. Cardiovasc Res 2020; 116:1767–1778.
87. Botta A, Laher I, Beam J, et al. Short term exercise induces PGC-1alpha, ameliorates inflammation and increases mitochondrial membrane proteins but fails to increase respiratory enzymes in aging diabetic hearts. PLoS One 2013; 8:e70248.
88. Chengji W, Xianjin F. Exercise protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway in rats. J Cell Physiol 2019; 234:1682–1688.
89. Veeranki S, Givvimani S, Kundu S, Metreveli N, Pushpakumar S, Tyagi SC. Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice. J Mol Cell Cardiol 2016; 92:163–173.
90. Searls YM, Smirnova IV, Fegley BR, Stehno-Bittel L. Exercise attenuates diabetes-induced ultrastructural changes in rat cardiac tissue. Med Sci Sports Exerc 2004; 36:1863–1870.
91. Hafstad AD, Lund J, Hadler-Olsen E, Hoper AC, Larsen TS, Aasum E. High- and moderate-intensity training normalizes ventricular function and mechanoenergetics in mice with diet-induced obesity. Diabetes 2013; 62:2287–2294.
92. Bo H, Jiang N, Ma G, et al. Regulation of mitochondrial uncoupling respiration during exercise in rat heart: role of reactive oxygen species (ROS) and uncoupling protein 2. Free Radic Biol Med 2008; 44:1373–1381.
93. Lew JK, Pearson JT, Saw E, et al. Exercise regulates microRNAs to preserve coronary and cardiac function in the diabetic heart. Circ Res 2020; 127:1384–1400.
94. Broderick TL, Poirier P, Gillis M. Exercise training restores abnormal myocardial glucose utilization and cardiac function in diabetes. Diabetes Metab Res Rev 2005; 21:44–50.
95. Stolen TO, Hoydal MA, Kemi OJ, et al. Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy. Circ Res 2009; 105:527–536.
96. Lerchenmuller C, Vujic A, Mittag S, et al. Restoration of cardiomyogenesis in aged mouse hearts by voluntary exercise. Circulation 2022; 146:412–416.
97. Campos JC, Queliconi BB, Bozi LHM, et al. Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure. Autophagy 2017; 13:1304–1317.
98. He C, Bassik MC, Moresi V, et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 2012; 481:511–515.
99. Okutsu M, Yamada M, Tokizawa K, et al. Regular exercise stimulates endothelium autophagy via IL-1 signaling in ApoE deficient mice. FASEB J 2021; 35:e21698.
100. Garatachea N, Santos-Lozano A, Sanchis-Gomar F, et al. Elite athletes live longer than the general population: a meta-analysis. Mayo Clin Proc 2014; 89:1195–1200.
101. Lee DC, Pate RR, Lavie CJ, Sui X, Church TS, Blair SN. Leisure-time running reduces all-cause and cardiovascular mortality risk. J Am Coll Cardiol 2014; 64:472–481.
102. O’Donovan G, Stamatakis E, Stensel DJ, Hamer M. The importance of vigorous-intensity leisure-time physical activity in reducing cardiovascular disease mortality risk in the obese. Mayo Clin Proc 2018; 93:1096–1103.
103. Wing RR, Jakicic J, Neiberg R, et al. Fitness, fatness, and cardiovascular risk factors in type 2 diabetes: look ahead study. Med Sci Sports Exerc 2007; 39:2107–2116.
104. Tanasescu M, Leitzmann MF, Rimm EB, Hu FB. Physical activity in relation to cardiovascular disease and total mortality among men with type 2 diabetes. Circulation 2003; 107:2435–2439.
105. Robinson AT, Franklin NC, Norkeviciute E, et al. Improved arterial flow-mediated dilation after exertion involves hydrogen peroxide in overweight and obese adults following aerobic exercise training. J Hypertens 2016; 34:1309–1316.
106. Ashor AW, Lara J, Siervo M, et al. Exercise modalities and endothelial function: a systematic review and dose-response meta-analysis of randomized controlled trials. Sports Med 2015; 45:279–296.
107. Maiorana A, O’Driscoll G, Cheetham C, et al. The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes. J Am Coll Cardiol 2001; 38:860–866.
108. Middlebrooke AR, Elston LM, Macleod KM, et al. Six months of aerobic exercise does not improve microvascular function in type 2 diabetes mellitus. Diabetologia 2006; 49:2263–2271.
109. Kim SH, Lee SJ, Kang ES, et al. Effects of lifestyle modification on metabolic parameters and carotid intima-media thickness in patients with type 2 diabetes mellitus. Metabolism 2006; 55:1053–1059.
110. Hambrecht R, Wolf A, Gielen S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342:454–460.
111. Laughlin MH, Bowles DK, Duncker DJ. The coronary circulation in exercise training. Am J Physiol Heart Circ Physiol 2012; 302:H10–23.
112. Jefferson ME, Nicklas BJ, Chmelo EA, et al. Effects of resistance training with and without caloric restriction on arterial stiffness in overweight and obese older adults. Am J Hypertens 2016; 29:494–500.
113. Pathak RK, Elliott A, Middeldorp ME, et al. Impact of CARDIOrespiratory FITness on arrhythmia recurrence in obese individuals with atrial fibrillation: the CARDIO-FIT Study. J Am Coll Cardiol 2015; 66:985–996.
114. Kitzman DW, Brubaker P, Morgan T, et al. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2016; 315:36–46.
115. Hayashino Y, Jackson JL, Hirata T, et al. Effects of exercise on C-reactive protein, inflammatory cytokine and adipokine in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Metabolism 2014; 63:431–440.
116. Ross R, Dagnone D, Jones PJ, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men: a randomized, controlled trial. Ann Intern Med 2000; 133:92–103.
117. Wong CY, Byrne NM, O’Moore-Sullivan T, Hills AP, Prins JB, Marwick TH. Effect of weight loss due to lifestyle intervention on subclinical cardiovascular dysfunction in obesity (body mass index >30 kg/m2). Am J Cardiol 2006; 98:1593–1598.
118. Marwick TH, Hordern MD, Miller T, et al. Exercise training for type 2 diabetes mellitus: impact on cardiovascular risk: a scientific statement from the American Heart Association. Circulation 2009; 119:3244–3262.
119. Arribat Y, Broskey NT, Greggio C, et al. Distinct patterns of skeletal muscle mitochondria fusion, fission and mitophagy upon duration of exercise training. Acta Physiol (Oxf) 2019; 225:e13179.
120. Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H. Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. Physiol Rep 2018; 6:e13651.
121. Dokladny K, Zuhl MN, Mandell M, et al. Regulatory coordination between two major intracellular homeostatic systems: heat shock response and autophagy. J Biol Chem 2013; 288:14959–14972.
122. Bonfante ILP, Monfort-Pires M, Duft RG, et al. Combined training increases thermogenic fat activity in patients with overweight and type 2 diabetes. Int J Obes (Lond) 2022; 46:1145–1154.
123. Brinkmann C, Przyklenk A, Metten A, et al. Influence of endurance training on skeletal muscle mitophagy regulatory proteins in type 2 diabetic men. Endocr Res 2017; 42:325–330.
124. Kruse R, Pedersen AJ, Kristensen JM, Petersson SJ, Wojtaszewski JF, Hojlund K. Intact initiation of autophagy and mitochondrial fission by acute exercise in skeletal muscle of patients with Type 2 diabetes. Clin Sci (Lond) 2017; 131:37–47.
125. Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett 2011; 585:1537–1542.
126. Alfaras I, Di Germanio C, Bernier M, et al. Pharmacological strategies to retard cardiovascular Aging. Circ Res 2016; 118:1626–1642.
127. Fontana L. Interventions to promote cardiometabolic health and slow cardiovascular ageing. Nat Rev Cardiol 2018; 15:566–577.
128. Mattison JA, Colman RJ, Beasley TM, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 2017; 8:14063.
129. Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009; 325:201–204.
130. Cohen K, Waldman M, Abraham NG, et al. Caloric restriction ameliorates cardiomyopathy in animal model of diabetes. Exp Cell Res 2017; 350:147–153.
131. Waldman M, Cohen K, Yadin D, et al. Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving ‘SIRT1 and PGC-1alpha’. Cardiovasc Diabetol 2018; 17:111.
132. Ruiz-Hurtado G, Garcia-Prieto CF, Pulido-Olmo H, et al. Mild and short-term caloric restriction prevents obesity-induced cardiomyopathy in young Zucker rats without changing in metabolites and fatty acids cardiac profile. Front Physiol 2017; 8:42.
133. AlGhatrif M, Watts VL, Niu X, et al. Beneficial cardiac effects of caloric restriction are lost with age in a murine model of obesity. J Cardiovasc Transl Res 2013; 6:436–445.
134. Makino N, Maeda T. Calorie restriction delays cardiac senescence and improves cardiac function in obese diabetic rats. Mol Cell Biochem 2021; 476:221–229.
135. Makino N, Oyama J, Maeda T, Koyanagi M, Higuchi Y, Tsuchida K. Calorie restriction increases telomerase activity, enhances autophagy, and improves diastolic dysfunction in diabetic rat hearts. Mol Cell Biochem 2015; 403:1–11.
136. Palee S, Minta W, Mantor D, et al. Combination of exercise and calorie restriction exerts greater efficacy on cardioprotection than monotherapy in obese-insulin resistant rats through the improvement of cardiac calcium regulation. Metabolism 2019; 94:77–87.
137. Guo Z, Mitchell-Raymundo F, Yang H, et al. Dietary restriction reduces atherosclerosis and oxidative stress in the aorta of apolipoprotein E-deficient mice. Mech Ageing Dev 2002; 123:1121–1131.
138. Zhao L, Zhang CL, He L, et al. Restoration of autophagic flux improves endothelial function in diabetes through lowering mitochondrial ROS-mediated eNOS monomerization. Diabetes 2022; 71:1099–1114.
139. de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease. N Engl J Med 2019; 381:2541–2551.
140. Wan R, Camandola S, Mattson MP. Intermittent food deprivation improves cardiovascular and neuroendocrine responses to stress in rats. J Nutr 2003; 133:1921–1929.
141. Pot GK, Almoosawi S, Stephen AM. Meal irregularity and cardiometabolic consequences: results from observational and intervention studies. Proc Nutr Soc 2016; 75:475–486.
142. Wennberg M, Gustafsson PE, Wennberg P, Hammarstrom A. Irregular eating of meals in adolescence and the metabolic syndrome in adulthood: results from a 27-year prospective cohort. Public Health Nutr 2016; 19:667–673.
143. Zarrinpar A, Chaix A, Panda S. Daily eating patterns and their impact on health and disease. Trends Endocrinol Metab 2016; 27:69–83.
144. Mattson MP, Allison DB, Fontana L, et al. Meal frequency and timing in health and disease. Proc Natl Acad Sci U S A 2014; 111:16647–16653.
145. Longo VD, Panda S. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab 2016; 23:1048–1059.
146. Ulgherait M, Midoun AM, Park SJ, et al. Circadian autophagy drives iTRF-mediated longevity. Nature 2021; 598:353–358.
147. Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventive and therapeutic intervention against diverse nutritional challenges. Cell Metab 2014; 20:991–1005.
148. Gill S, Le HD, Melkani GC, Panda S. Time-restricted feeding attenuates age-related cardiac decline in Drosophila. Science 2015; 347:1265–1269.
149. Melkani GC, Panda S. Time-restricted feeding for prevention and treatment of cardiometabolic disorders. J Physiol 2017; 595:3691–3700.
150. Hatori M, Vollmers C, Zarrinpar A, et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab 2012; 15:848–860.
151. Sherman H, Genzer Y, Cohen R, Chapnik N, Madar Z, Froy O. Timed high-fat diet resets circadian metabolism and prevents obesity. FASEB J 2012; 26:3493–3502.
152. Hou T, Su W, Duncan MJ, Olga VA, Guo Z, Gong MC. Time-restricted feeding protects the blood pressure circadian rhythm in diabetic mice. Proc Natl Acad Sci U S A 2021; 118:e2015873118.
153. Meyer TE, Kovacs SJ, Ehsani AA, Klein S, Holloszy JO, Fontana L. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol 2006; 47:398–402.
154. Riordan MM, Weiss EP, Meyer TE, et al. The effects of caloric restriction- and exercise-induced weight loss on left ventricular diastolic function. Am J Physiol Heart Circ Physiol 2008; 294:H1174–1182.
155. Lefevre M, Redman LM, Heilbronn LK, et al. Caloric restriction alone and with exercise improves CVD risk in healthy nonobese individuals. Atherosclerosis 2009; 203:206–213.
156. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A 2004; 101:6659–6663.
157. van Eyk HJ, van Schinkel LD, Kantae V, et al. Caloric restriction lowers endocannabinoid tonus and improves cardiac function in type 2 diabetes. Nutr Diabetes 2018; 8:6.
158. Fontana L, Villareal DT, Weiss EP, et al. Calorie restriction or exercise: effects on coronary heart disease risk factors: a randomized, controlled trial. Am J Physiol Endocrinol Metab 2007; 293:E197–E202.
159. Most J, Gilmore LA, Smith SR, Han H, Ravussin E, Redman LM. Significant improvement in cardiometabolic health in healthy nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance. Am J Physiol Endocrinol Metab 2018; 314:E396–E405.
160. Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 2006; 295:1539–1548.
161. Kroeger CM, Klempel MC, Bhutani S, Trepanowski JF, Tangney CC, Varady KA. Improvement in coronary heart disease risk factors during an intermittent fasting/calorie restriction regimen: relationship to adipokine modulations. Nutr Metab (Lond) 2012; 9:98.
162. Stein PK, Soare A, Meyer TE, Cangemi R, Holloszy JO, Fontana L. Caloric restriction may reverse age-related autonomic decline in humans. Aging Cell 2012; 11:644–650.
163. Ruggenenti P, Abbate M, Ruggiero B, et al. Renal and systemic effects of calorie restriction in patients with Type 2 diabetes with abdominal obesity: a randomized controlled trial. Diabetes 2017; 66:75–86.
164. Mercken EM, Crosby SD, Lamming DW, et al. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell 2013; 12:645–651.
165. Yang L, Licastro D, Cava E, et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep 2016; 14:422–428.
166. Harvie MN, Pegington M, Mattson MP, et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes (Lond) 2011; 35:714–727.
167. Moro T, Tinsley G, Bianco A, et al. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. J Transl Med 2016; 14:290.
168. Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson CM. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab 2018; 27:1212–1221. e1213.
169. Wilkinson MJ, Manoogian ENC, Zadourian A, et al. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab 2020; 31:92–104. e105.
170. Hoddy KK, Kroeger CM, Trepanowski JF, Barnosky A, Bhutani S, Varady KA. Meal timing during alternate day fasting: impact on body weight and cardiovascular disease risk in obese adults. Obesity (Silver Spring) 2014; 22:2524–2531.
171. Madeo F, Pietrocola F, Eisenberg T, Kroemer G. Caloric restriction mimetics: towards a molecular definition. Nat Rev Drug Discov 2014; 13:727–740.
172. Eisenberg T, Abdellatif M, Schroeder S, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 2016; 22:1428–1438.
173. Pucciarelli S, Moreschini B, Micozzi D, et al. Spermidine and spermine are enriched in whole blood of nona/centenarians. Rejuvenation Res 2012; 15:590–595.
174. Sciarretta S, Zhai P, Shao D, et al. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 2012; 125:1134–1146.
175. Das A, Durrant D, Koka S, Salloum FN, Xi L, Kukreja RC. Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J Biol Chem 2014; 289:4145–4160.
176. Sulaiman M, Matta MJ, Sunderesan NR, Gupta MP, Periasamy M, Gupta M. Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 2010; 298:H833–843.
177. Zheng J, Cheng J, Zheng S, Feng Q, Xiao X. Curcumin, a polyphenolic curcuminoid with its protective effects and molecular mechanisms in diabetes and diabetic cardiomyopathy. Front Pharmacol 2018; 9:472.
178. Wu Y, Xia ZY, Zhao B, et al. (−)-Epigallocatechin-3-gallate attenuates myocardial injury induced by ischemia/reperfusion in diabetic rats and in H9c2 cells under hyperglycemic conditions. Int J Mol Med 2017; 40:389–399.
Keywords:

calorie restriction; cardiometabolic diseases; diabetes; exercise; obesity

© 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.